Project Summary Traumatic brain injury (TBI) results from mechanical forces applied to the head. Ensuing cascades of complex pathophysiology transition the injury event into a disease process. The protracted nature of disease dissuades continued pharmacological interventions in favor of rehabilitation strategies to alleviate neurological impairment. The enduring constellation of emotional, somatic, and cognitive impairments degrade quality of life for the millions of TBI survivors suffering from long-term neurological symptoms, and countless more remain undiagnosed. For these individuals, including a significant percentage of our Veterans, effective therapeutic interventions are desperately needed. With this clinical problem in mind, rehabilitation strategies have reported mixed results, as most have not focused on specific symptomatology or explored cellular processes. In rodent models of diffuse TBI, a late-onset, long-lasting sensory sensitivity to whisker stimulation develops over time, similar to the protracted onset of light and sound sensitivity in TBI survivors. In addition, experimental diffuse TBI causes clinically-relevant impairment in short term, long term, and working memory. Therefore, laboratory studies provide a platform to evaluate efficacy and mechanism of rehabilitation strategies to mitigate neurological symptoms after diffuse brain injury. In this proposal, we test the hypothesis that therapeutic efficacy of TBI rehabilitation depends on regional activation during rehabilitation task performance. It follows that temporary pharmacological inactivation during rehabilitation would eliminate therapeutic efficacy and associated transformations to relevant brain circuits. To test the hypothesis, adult, male and female rats receive a diffuse brain or sham injury by midline fluid percussion. Aim 1 addresses whether tactile exploration and spatial navigation through a peg forest rehabilitation environment for three weeks after 1 month post-injury alleviates sensory sensitivity and cognitive impairment at two and three months post-injury. Preliminary data indicate peg forest rehabilitation improves both neurological symptoms, whereas an open field rehabilitation only improves sensory sensitivity. Aim 2 identifies brain regions activated by rehabilitation and demonstrates the inactivation by local GABA-A agonist muscimol administration as measured by cFos expression levels. Aim 3 inactivates associated brain regions (S1BF, hippocampus) to determine whether regional activation is necessary for rehabilitation therapeutic efficacy. Aim 4 quantifies rehabilitation-related neuropathology and cellular morphology in associated sensory and cognitive circuitry. Expected outcomes would show therapeutic efficacy of peg forest rehabilitation on somatosensory and cognitive outcome measures above open field rehabilitation and caged control animals, which depended on regional activation and underlying remodeling of circuit structure. The impact of these studies is a firm foundation to promote rehabilitation strategies, rather than rest, in the recovery from TBI.